Most healthy individuals are persistently infected with the human polyomavirus JC (JCPyV) without significant consequences, yet in immunocompromised hosts, JCPyV can cause an often fatal disease -- progressive multifocal leukoencephalopathy (PML). There is currently no effective treatment to prevent or treat PML and novel immune-based therapies are urgently needed to decrease the morbidity and mortality associated with PML. Classically, natural killer (NK) cells are viewed as nonspecific effector cells of the innate immune system that play critical roles in defense against viral infections. Unexpectedly, it was recently demonstrated that besides their ability to rapidly eliminate virus-infected cells without the need for prior antigen sensitization, NK cells also exhibit adaptive immune functions. Different forms of adaptive capabilities have been identified among human NK cell subpopulations, including reports of true antigen-specific memory NK cells as well as adaptive NK cells with enhanced antibody-dependent functions. Adaptive NK cell subsets are endowed with potent anti-viral properties and protection mediated by virus-specific memory NK cells has been demonstrated in mouse models. Importantly, increasing evidence suggest that NK cell can mediate anti-viral responses to JCPyV. In particular, our preliminary data now show potent responses to JCPyV peptides by NK cells, isolation and cloning of single JCPyV-specific NK cells, and reduced JCPyV-specific antibody-dependent cellular cytotoxicity in PML patients. Based on these data, we hypothesize that NK cells and antibodies eliciting NK cell responses play a role in JCPyV pathogenesis. Specifically, we propose to build on our preliminary data to investigate the overarching hypothesis that specific subsets of NK cells can mediate potent anti-viral responses against JCPyV and protect immunocompromised patients against PML, through two focused independent Aims: (i) Define mechanisms crucial to control of JCPyV by NK cells; and (ii) Evaluate the role played by JCPyV-specific antibodies in modulating NK cell activity against JCPyV. If successful, the results of these innovative studies will contribute new knowledge of human immune response against JCPyV and provide the rationale to develop novel immunotherapeutic approaches to harness NK cell function against JCPyV.